Stable hyperforin salts, method for producing same and their use in the treatment of alzheimer&#39;s disease

ABSTRACT

Described are salts of hyperforin and adhyperforin of formula Iwherein m is an integer from 1 to 3, p is equal to m and gives the total number of positive charges of the residue [B],[A-] is an anion of formula II with n=0 or 1and [B]p+ is an ion of an alkali metal or an ammonium ion of a salt-forming nitrogen base of formula IIIwherein R1 through R4 have a variety of meanings including hydrogen, alkyl, cycloalkyl and similar groups which in turn may be substituted with one or more substituents. The salts serve inter alia for enriching or purifying hyperforin and adhyperforin from St. John&#39;s Wort extracts. Pharmaceutical preparations containing the salts are used for treating Alzheimer&#39;s Disease.

SUBJECT OF THE INVENTION

The subject of the invention is the provision of stable salts ofhyperforin and adhyperforin which are capable of pharmacologicalactivity as they are or by release of the hyperforin or adhyperforin. Afundamental aspect of the invention relates to the provision of a methodof enriching or purifying hyperforin and adhyperforin from extracts ofSt. John's wort by means of precipitation in the form of these stablesalts. Another especially important subject of the invention comprisesthe provision of new active substances for controlling Alzheimer'sdisease (hereinafter abbreviated to “AD”) by treating the cause of thedisease.

A further important aspect of the present invention relates to theprovision of active-substance combinations which can be used to treatthe cause of AD, and at the same time eliminate, considerably improve,or at least halt the progression of psychopathological concomitantphenomena which frequently arise in association with AD, such asanxiety, depressive illnesses, and cognitive disturbances.

BACKGROUND OF THE INVENTION

The amyloid peptide Aβ1-42, a processed product of Alzheimer PrecursorProtein APP, plays a central role in the occurrence of AD [Lamb, B. T.:Presenilins, amyloid-β and Alzheimer's Disease. Nature Med. 3 (1997)28-29. Selkoe, D. J.: Alzheimer's Disease: Genotypes, Pheno-type, andTreatments. Science 275 (1997) 630-631]. This hypothesis is supported bythe following experimental findings:

APP Missense mutations (patients with familial AD) lead to an increasedrelease of Aβ1-42 [Scheuner, D. et al.: Secreted amyloid β-proteinsimilar to that in the senile plaques of Alzheimer's disease isincreased in vivo by the presenilin 1 and 2 and APP mutations linked tofamilial Alzheimer's disease. Nature Med. 2 (1996) 864-870].

Mutations in presenilin 1 and presenilin 2 (patients with familial AD)similarly lead to an increase in released Aβ1-42 [Scheuner, D. et al].Transgenic mice, which overexpress mutated APP, develop age-dependentdeposits of Aβ and show cognitive disturbances [Games, D. et al.:Alzheimer-type neuropathology in transgenic mice overexpressing V717Fβ-amyloid precursor protein. Nature 373 (1995) 523-527. Hsiao, K. etal.: Correlative memory deficits, Aβ Elevation, and Amyloid Plaques inTransgenic Mice. Science 274 (1996) 99-102].

The proteolytic cleavage of the pathogenic Aβ from the AlzheimerPrecursor Protein APP is mediated by β- and γ-secretase, the molecularidentity of which is unknown. α-Secretase processes APP to a solubleform (sAPP) and a cytoplasmatic residue. The cleavage of α-secretaselies within Aβ, with the result that in this case no pathogenic Aβarises. The molecular identity of α-secretase is similarly unknown.

α-Secretase is stimulated by acetylcholine, mediated by the muscarinicreceptors m1 and m3 [Nitsch, R. M. et al.: Release of Alzheimer amyloidprecursor derivatives stimulated by activation of muscarinicacetylcholine receptors. Science 258 (1992) 304-307]. The cellularmediator is protein kinase C (“PKC”). This is also confirmed byexperiments which, following direct stimulation of PKC by phorbol ester,reach the same result [Buxbaum, J. D. et al.: Processing of Alzheimerbeta/A4 amyloid precursor protein: Modulation by agents that regulateprotein phosphorylation. Proc. Natl. Acad. Sci. USA 87 (1990)6003-6006].

Tacrine, the most successful therapeutic agent to date against AD is anacetylcholine inhibitor [Giacobini, E.: Cholinomimetic therapy ofAlzheimer disease: Does it slow down deterioration? In Recent Advancesin the Treatment of Neurodegenerative Disorders and CognitiveDysfunction, Int. Acad. Biomed. Drug Res. 7 (1994) 51-57. Racagni, G. etal., eds. Basel: Karger].

This may be interpreted as indirect stimulation of α-secretase by thefollowing signal chain: Tacrine inhibits acetylcholinesterase. Theconcentration of acetylcholine is thereby increased. Acetylcholineactivates the PKC via the muscarinic receptors m1 and m3. By this meansthe activity of α-secretase is increased. In consequence the quantity ofpathogenic Aβ is lowered.

From these findings it can be concluded that selective activation of PKCcan be an effective therapeutic starting point to inhibiting theproduction of amyloidogenic Aβ and thus to the treatment of AD. Since,of all 11 PKC isoenzymes, the γ-form is the only sub-type to beexpressed exclusively in neuronal cells, substances which stimulatePKC-γ represent a new starting point to the therapy of AD. Moreover, allsubstances or processes which stimulate α-secretase or inhibit β- andγ-secretase are suitable for preventing the release of pathogenic Aβ andthus for treating the cause of AD.

STATE OF THE ART

The phloroglucin derivative hyperforin is one of the principalingredients in fresh St. John's wort. It is associated with itshomologue adhyperforin in a lower concentration. As both substances arehighly unstable to light and the influence of air, their contentdeclines even when the fresh plant is dried. By fast and careful dryingfollowed by suitable extraction methods, extracts with a content ofabout 3-60% hyperforin/adhyperforin can be obtained [DE 19619512 C1].

However, without addition of appropriate stabilisers, hyperforin is notstable, and can therefore be obtained and stored in an enriched or pureform only by use of expensive techniques.

Reference has already been made to the importance of hyperforin forachieving the antidepressant efficacy of St. John's wort extracts inEP-A-0599307. Since then it has been scientifically proven that, on thebasis of its pharmacological profile, hyperforin exerts a considerableinfluence in the medical treatment of depression and otherserotonin-dependent diseases [S. S. Chatterjee et al., hyperforin andhypericum extract, Interactions with some Neurotransmitter Systems(SL-82), 2nd Intern. Congress on Phytomedicine, Sep. 11-14, 1996,Munich. See also: Pharmacopsychiatry 1998, 31 Suppl. I, 1-60].

Alzheimer's dementia (AD) is a serious disease of gradual onset whichaffects a considerable proportion of the population especially theelderly. It is characterised by initial forgetfulness, then increasingmemory disturbances and losses of other cognitive abilities. Itconcludes with complete mental degeneration and loss of personality, andtakes an ultimately fatal course. To date, no satisfactory,cause-orientated therapy for AD is available [K. Mendla, DieAlzheimer-Krankheit: Neue Ansätze in der Pharmakotherapie (1996).Pharm.Ztg. 141, 351-356].

TECHNICAL PROBLEM

The technical problem underlying the invention thus consists in the factthat, firstly, there is no known technically satisfactory method forobtaining and stabilising pure or greatly enriched hyperforin andadhyperforin, severely impeding the isolation, storage and use of thesesubstances; secondly, there is a deficiency of active substances for thecause-orientated therapy of Alzheimer's disease, resulting in massivefinancial outlays within the social services. The problem of theinvention is to help eliminate these defects.

SOLVING THE TECHNICAL PROBLEM

This problem is resolved according to the invention by

the new salts of hyperforin and adhyperforin according to patent claims1 to 5;

the method of manufacturing these salts according to Claim 6;

the method of enriching or purifying hyperforin and adhyperforin in theform of these salts according to Claims 7 and 8;

the use of these salts for maintaining stable stocks of hyperforin,adhyperforin and their mixtures according to Claim 9;

the pharmaceutical preparation according to Claim 10, and

the new use of hyperforin, adhyperforin and their mixtures as medicinalproducts for the treatment of AD (2^(nd) medical indication).

It was surprisingly found that the instability of hyperforin or ofadhyperforin can be completely eliminated or at least considerablyreduced by conversion of the substance into suitable salts of generalformula I

[A⁻]_(m)[B]^(p+)  (I)

No salts of hyperforin are known to date.

In formula I, m is a whole number from 1 to 3 and [A⁻] is the anion ofhyperforin or adhyperforin, where n=0 or 1 (general formula II):

and [B]^(p+) is either

an ion of an alkali metal, preferably Li⁺, Na⁺ or K⁺, where p=1, or anammonium ion of a salt-forming nitrogen base of general formula III

 wherein the residues R1, R2 and R3,

independently of one another, are a hydrogen atom, a straight-chain orbranched alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, alkenyl,alkynyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl orheteroarylalkyl group, or a derivative of the said groups substitutedwith one or more hydroxy, alkoxy, aryloxy, alkanoyl, aroyl, carboxy,alkoxycarbonyl, amino, alkylamino, hydroxylamino, amido, carbamoyl,ureido, amidino, guanidino, cyano, azido, mercapto, alkylthio,alkylsulphoxy, alkylsulphonyl, alkylsulphenyl, aminosulphonyl, fluoro,chloro, bromo, iodo, alkyl or perfluoroalkyl residue(s),

 or wherein the residues R1 and R2

together with the N atom are an azetidine, pyrrolidine, pyrroline,piperidine, piperazine, homopiperazine, morpholine, thiomorpholine,pyridine, di- or tetrahydropyridine, pyrimidine, pyrazine, azepine,dihydroazepine, oxazepine, diazepine, imidazole, pyrazole, oxazole, orthiazole ring, or one of the said rings which exhibits aliphatic,heteroaliphatic, aromatic or heteroaromatic rings condensed on to itand/or is substituted with one or more hydroxy, alkoxy, aryloxy,alkanoyl, aroyl, carboxy, alkoxycarbonyl, amino, alkylamino,hydroxylamino, amido, carbamoyl, ureido, amidino, guanidino, cyano,azido, mercapto, alkylthio, alkylsulphoxy, alkysulphonyl,alkylsulphenyl, aminosuiphonyl, fluoro, chloro, bromo, iodo, alkyl orperfluoroalkyl residue(s),

 and wherein the residue R4

is a hydrogen atom or a straight-chain or branched alkyl group, in whichp=m and gives the total number of positive charges of the residue [B].

The N,N-dicyclohexylamine salts of hyperforin and adhyperforin and theirmixtures are especially preferable.

From the above definition of the base B serving as a salt-former itemerges that a large number of basic compounds of nitrogen are suitablefor satisfactorily increasing the stability of hyperforin oradhyperforin, both of which are unstable in the uncharged form.

Suitable bases are e.g.:

aliphatic and cycloaliphatic amines or polyamines such as mono-, di-, ortri-(C₃ to C₂₀)alkylamines, aminoethanol, methylaminoethanol,dimethylaminoethanol, choline, 2-hydroxy-1,1-dimethylethylamine,tris(hydroxymethyl)methylamine, N-methyl-D-glucamine, ethylenediamine,dicylohexylamine, N-cyclohexyl-N-3-aminopropylamine, 1-aminoadamantaneor 1-amino-3,5-dimethyladamantane, optionally substituted with one ormore hydroxyl groups,

cyclic or heterocyclic amines such as pyrrolidine, piperidine,morpholine, piperazine, N-methylpiperazine or N-methylhomopiperazine,optionally substituted with one or more lower alkyl- (=C₁ to C₄-alkyl)or hydroxyl residues,

possibly substituted aromatic, heteroaromatic, arylaliphatic orheteroarylaliphatic amines such as benzylamine,3,4,5-trimethoxybenzylamine, veratrylamine, phenethylamine,homoveratrylamine, N-methylhomoveratrylamine, 4-aminopyridine, tacrineand analogues, imipramine, desipramine, selegiline, nicotine, pindolol,

amino acid esters and amides such as methyl, ethyl, propyl or isopropylesters and amides of glycine, alanine, phenylalanine, leucine,isoleucine, methionine, proline, valine, sarcosine, pipecolic acid,

as well as basic amino acids such as lysine or arginine or their amides.

Bases which are especially suitable are those that are themselves activesubstances and have the same medical indications as hyperforin, orsupport its therapeutic use. Those coming into consideration areprimarily basic active substances with the indications:

Alzheimer's Disease (AD), e.g.

Acetylcholinesterase inhibitors (e.g. amiridine, donezepil, ensaculine,eptastigmine, galanthamine, huperzine A, 7-methoxytacrine,physostigmine, SDZ-ENA-713 (Exelon), SM-10888, suronacrine, tacrine,velnacrine), cholinergic activators, NMDA antagonists (e.g. memantine),glutamine-receptor antagonists, serotonin agonists and antagonists (e.g.adatanserin), monoamine oxidase inhibitors (e.g. tranylcypromine,selegelin), PKC activators and α-secretase inhibitors, tyrosine kinaseantagonists, muscarinic agonists (e.g. arecoline, BIBN 99, itameline,milameline, talsaclidine, xanomeline, YM796),

Antidepressants, e.g.

amitryptiline, dibenzepin, desipramine, desitryptiline, doselupine,doxepin, clomipramine, fluoxetine, fluvoxamine, imipramine, lofepramine,maprotiline, moclebemide, mianserin, nortriptyline, opipramol,paroxetine, tranylcypromine, trazodone, trimipramine, viloxazine,

Anxiolytics, e.g.

chlorprothixene, dixyrazine, fluphenazine, levomepromazine, melperone,perphenazine, promazine, promethazine, pritiphendyl, sulpiride,tandospirone, thioridazine, trifluoperazine, zuclopenthixol,

Calcium antagonists (with basic side chain) e.g.

amlodipine, azelnidipine, bamidipine, benidipine, cronidipine,edrecolomab (AE0047), efonidipine, elgodipine, lercanidipine,manidipine, nicardipine, palodipine, verapamil,

Dyspepsia therapeutic agents and prokinetics, e.g.

cisapride, metoclopramide, renzapride (5-HT₄ agonists),

β-receptor blockers, e.g.

atenolol, alprenolol, carazolol, propranolol, labetalol, mepindolol,metoprolol, oxprenolol, penbutolol, pindolol, bupranolol, bunitrolol,metipranolol, nadolol,

Nootropics, e.g.

lomerizine, nebracetam, pramiracetam, SNK-882.

Salts of hyperforin and adhyperforin with basic active substances ofthis type form an especially innovative partial aspect of the presentinvention, as they not only increase the stability of thetherapeutically active hyperforin, but also, in consequence of theirintrinsic therapeutic action, allow an especially appropriatecombination of mutually potentiating or mutually supporting activeprinciples.

MANUFACTURE OF THE SALTS ACCORDING TO THE INVENTION

The salts according to the invention can be manufactured in variousways. In the following explanation of the method, the term “hyperforin”in all cases also means the homologue adhyperforin and mixtures of thetwo substances. “Lower” always means “C₁ to C₄-”.

Method A: Hyperforin is dissolved in a lower alkanol (e.g. methanol,ethanol, propanol or isopropanol), preferably under protective gas andwith exclusion of light, reacted with the solution of an equimolarquantity of alkali-metal hydroxide or alkali-metal lower alkoxide (e.g.sodium methoxide or ethoxide) in one of the above-mentioned loweralkanols, the solution is evaporated, taken up with water andlyophilised. Stable, colourless to cream-coloured alkali salts ofhyperforin are obtained in the form of a powder. Alternatively thehyperforin can also be dissolved directly in the solution of the alkalimetal lower alkoxide and worked up as above.

Method B: Hyperforin is dissolved in an aprotic solvent selected fromthe group of apolar C₁-C₁₀ alkanes and C₁-C₁₀ cycloalkanes e.g. pentane,hexane, heptane, octane, isooctane, or cyclohexane, optionally withaddition of small quantities of a lower alkanol (e.g. methanol, ethanol,or isopropanol), preferably under protective gas and with exclusion oflight, this solution is reacted with the equimolar quantity of the basiccomponent B or with a solution of the same in one of the above-mentionedsolvents or in a lower halogenoalkane, e.g. dichloromethane orchloroform, or in a lower ether, e.g. diethyl ether, diisopropyl ether,tert.-butyl methyl ether or tetrahydrofuran, or in a lower ketone, e.g.acetone or methyl ethyl ketone, the mixture concentrated if necessary,the precipitating salt separated, if necessary recrystallised, and driedunder vacuum. Crystalline or amorphous ammonium salts of hyperforin areobtained in the form of a powder.

If the base B contains more than one basic centre capable of saltformation, if desired correspondingly smaller quantities, e.g. ½ or⅓-molar quantities of base B may be used, so that the hyperforin/baseratio is m/p.

Method C: Hyperforin is dissolved in a lower alkanol (e.g. methanol,ethanol, or isopropanol), preferably under protective gas and withexclusion of light, this solution is reacted with the equimolar quantityof the basic component B or with a solution of the same in one of theabove-mentioned solvents, the mixture is evaporated, taken up in water,and lyophilised. Crystalline or amorphous ammonium salts of hyperforinare obtained in the form of a powder.

Method D: Hyperforin is dissolved in a lower alkanol (e.g. methanol,ethanol, or isopropanol), preferably under protective gas and withexclusion of light, this solution is reacted with an equimolar quantityof the basic component B in water, the lower alcohol is removed bydistillation under vacuum, and the remaining aqueous mixture islyophilised, if necessary after addition of water. The powdery saltobtained is if necessary re-crystallised from a lower alcohol,alcohol/water mixture or from a lower ester.

Method for the Enrichment or Pure Isolation of Hyperforin andAdhyperforin From St.-John's Wort Extracts

To date the purification of hyperforin from St.-John's wort extract hasbeen possible only with the use of very expensive chromatographicmethods which were furthermore made technically unacceptable by the highinstability of hyperforin and its homologue to light and to the oxygenin air (P. Maisenbacher, Universität Tübingen, Diss. 1991. R.Burgdörfer, Universität Marburg, Diss. 1987).

A surprisingly simple and cost-reducing solution to this technicalproblem has now been found which consists in dissolving St.-John's wortextracts, e.g. a CO₂ extract with a 20-80% hyperforin/adhyperforincontent, in a suitable solvent selected from the series of apolar C₁-C₁₀alkanes and cycloalkanes, e.g. pentane, hexane, heptane, octane,iso-octane, or cyclohexane, optionally with addition of small quantitiesof a lower alkanol (e.g. methanol, ethanol or isopropanol), preferablyunder protective gas and with exclusion of light, this solution isreacted with the at least equimolar quantity of the basic component B ora solution of the same in one of the above-mentioned solvents or in alower halogenoalkane, e.g. dichloromethane or chloroform, or in a lowerether e.g. diethyl ether, diisopropyl ether, tert.-butylmethyl ether ortetrahydrofuran, or in a lower ketone, e.g. acetone or methyl ethylketone, the mixture is concentrated if necessary, the precipitating saltis separated, if necessary re-precipitated and/or re-crystallised anddried under vacuum. Crystalline or amorphous ammonium salts ofhyperforin/adhyperforin or of a mixture of them are obtained in the formof a powder.

Salt-forming amines especially suitable for this method arecycloaliphatic (e.g. dicyclohexylamine) araliphatic (e.g. benzylamineand its methoxy-substituted derivatives), heterocyclic or heteroaromaticamines (e.g. 4-aminopyridine).

Hyperforin/adhyperforin can be readily obtained in a pure form from thecrystalline and storage-stable salts by acidification, preferably withan organic acid (e.g. citric acid or tartaric acid), and subsequentdistribution between one of the listed solvents and water, and eitherused as they are or transferred to other desired salts. To this end thehyperforin salt is dissolved or suspended in the selected solvent (e.g.methyl-tert.butyl ether or ethyl acetate), under a protective-gasatmosphere and exclusion of light, reacted with the at least equimolarquantity of the acid dissolved in water, stirred until completelydissolved, the aqueous phase is separated, and the organic phase isevaporated gently after washing with water.

Medicinal Products

The present invention further relates to medicinal products which, inaddition to non-toxic, inert pharmaceutically suitable carriersubstances, also contain one or more of the hyperforin and/oradhyperforin salts according to the invention, or which consist of oneor more of the hyperforin and/or adhyperforin salts, as well as methodsof manufacturing these medicinal products.

Non-toxic, inert pharmaceutically suitable carrier substances are to beunderstood as solid, semi-solid or liquid diluents, fillers andformulation adjuvants of all kinds.

Suitable solid or liquid galenical preparations of the medicinalproducts according to the invention are e.g. tablets, capsules,sugar-coated tablets, suppositories, syrups, emulsions, suspensions,drops or injectable solutions, as well as products with slow release ofthe active substance.

As carriers or diluents one should name e.g. various sugars or starches,cellulose derivatives, magnesium carbonate, gelatins, oils of animal orvegetable origin, polyethylene glycols, water or other physiologicallysafe solvents, as well as water-containing buffers, which may berendered isotonic by addition of salts or glucose. Surfactantsubstances, colourings, flavourings, stabilisers and preservatives mayalso find a use as further additives in the medicinal products accordingto the invention.

The therapeutically effective compounds are present in the medicinalproducts listed above preferably in a concentration of about 0.5 to 95%of the overall mixture.

The medicinal products are manufactured using methods familiar to theperson skilled in the art, e.g. by mixing of the active substance(s)with the carrier substances and additives and further processing toproduce the desired galenical form.

The invention also relates to the use of the active substances of theinvention, and of the medicinal products manufactured from them, inhuman medicine for the therapy or prophylaxis of Alzheimer's disease.

Finally, the invention relates to the use of the substances hyperforinand/or adhyperforin, known ingredients of extracts used for therapeuticpurposes, if necessary together with a pharmaceutically safe carrier ordiluent, in human medicine for the therapy or prophylaxis of Alzheimer'sdisease (2nd medical indication)

The active substances or medicinal products of the invention may beadministered orally, parenterally, intravenously and/or rectally. Inhuman medicine, the active substances are preferably administered indoses amounting in total to 0.01 to 10, in particular 0.05 to 5 mg/kgbody weight per 24-h period, if necessary in the form of several unitdoses. The total amount is administered in 1 to 5, preferably in 1 to 3unit doses. The dosage and timing of the doses, and the choice ofappropriate mode of administration can easily be accomplished by anyoneskilled in the art on the basis of his or her scientific knowledge.

The following examples are intended to illustrate the invention withoutlimiting its scope.

General: Melting points were measured with Elektrothermal® or B-545(Büchi) apparatus; IR spectra were recorded with an IFS 28 (Bruker)IR-spectrometer on KBr blanks, NMR spectra with an AC 200 or Avance 200(Bruker) in D₄-methanol (200 MHz for ¹H and 50 MHz for ¹³C; δ-values inppm). HPLC determinations were performed using a Dynamax PDA-1 fromRainin, Voburn, Mass., USA. HPLC conditions (isocratic): adsorbant:Eurospher 100-C18, 10 μm. Eluant: Acetonitrile/water/phosphoricacid=85/15/0.3 (vol./vol.). Detection: 273 nm. Reference standard:Hyperforin dicyclohexylamine salt according to example 2b=100%. Assay:Content stated in area-% with reference to the reference standard.Stated contents of hyperforin (adhyperforin) in their salts are in allcases given as a percentage of the stoichiometric proportion ofhyperforin (adhyperforin). Solvent: Methanol (p.a. or ultra pure),methyl-tert.butyl ether (>99%), isopropanol (>99%) and water(bidistilled) are degassed prior to use. Operating conditions: under redlight or in darkened apparatus under protective gas (nitrogen or argon).Elementary analysis: lyophilised products occasionally contain residualwater. They are calculated as hydrates. Abbreviations: MTBE=Methyltert.-butyl ether. “98H/I”=n-heptane/isopropanol 98/2 (vol/vol).Mp.=melting point. anh.=anhydrous. Th=theoretical. sv=very strong.

EXAMPLE NO. 1a

Method A

Hyperforin Sodium Salt.

23 mg (1 mmol) sodium is dissolved in 50 ml anhydrous methanol. 536 mg(1 mmol) hyperforin is dissolved in this solution under stirring, andthe solution evaporated. The residue is dissolved in 100 ml water andlyophilised. Yield: 556 mg of a light-coloured powder (99.6% oftheoretical). Mp.: Degradation from 170° C. IR: 1420-1500 cm⁻(sv).

EXAMPLE NO. 1b

Method A

Hyperforin Sodium Salt.

728.5 mg (1.31 mmol) 96.5% hyperforin is dissolved in 80 ml methanol,reacted with 5.1 ml (1.32 mmol) 0.259-molar methanolic sodium hydroxidesolution, allowed to stand for a short time, and the solution evaporatedat 50° C. The residue is dissolved in water and lyophilised. Yield:746.7 mg of a white powder (101% of theoretical). Mp.: Sintering between90° C. and 110° C., degradation at 170° C. IR: 1449 cm⁻¹ (sv, broad).¹H-NMR: no impurities apart from approx. 1.4 mol % (0.08 weight-%)methanol visible. C₃₅H₅₁NaO₄ (558.78). Calculated/recovered: C(75.23/71.61), H (9.20/8.87); Na (4.11/4.6). Hyperforin content (HPLC):86.5%.

EXAMPLE NO. 2a

Method B

N,N-Dicyclohexylamine Salt of Hyperforin.

1 g (1.86 mmol) hyperforin is dissolved in 50 ml n-pentane/methanol 98/2vol/vol, reacted with 445 μl (2.33 mmol) dicyclohexylamine and allowedto stand for 10 h at 4° C. Precipitated product is drawn off by suctionover a sintered glass filter, washed with pentane and dried under vacuumat room temperature. Yield: 652 mg of a white powder (48.7% oftheoretical). Mp.: 157.2° C. IR: 1473, 1489 cm⁻¹ (sv). C₄₇H₇₅NaO₄(718.13). Calculated/recovered: C (78.61/76.91), H (10.53/10.42); Na(1.95/1.70). NMR: In addition to the signals of hyperforin, thefollowing signals of dicyclohexylamine are visible: ¹H-NMR: 3.15 (m; 2H; 1-CH) and (partially overlapping) 1.82-2.08 (m, 2- and 6-CH₂), 1.42(quint, 3-, 4-, and 5-CH₂). Dicyclohexylamine/hyperforin quotient=1/1.No visible impurities. ¹³C-NMR: 54.65 (1-CH), 30.72 (2- and 6-CH₂, 26.06(4-CH₂) and 25.64 (3- and 5-CH₂) The substance is recrystallised frompentane/methanol. Mp.: 163.9° C. C₄₇H₇₅NO₄ (718.13).Calculated/recovered: C (78.61/78.92), H (10.53/10.44); N (1.95/1.79).Hyperforin content (HPLC): 1 00%.

EXAMPLE NO. 2b

Method B

N,N-dicyclohexylamine Salt of hyperforin.

1.547 g (2.82 mmol) 98% hyperforin is dissolved in 60 mln-heptane/isopropanol 98/2 vol/vol, reacted with 600 μl (3.0 mmol)dicyclohexylarnine and allowed to stand for 18 h under N₂ at roomtemperature. Precipitated product is drawn off by suction over asintered glass filter, washed with heptane and dried under vacuum atroom temperature for 8 h. Yield: 1.767 g (2.46 mmol) of a white powder(87% of theoretical). Mp.: 159.7° C. IR: 1473, 1489 cm⁻¹ (sv). ¹H-NMR:corresponds to the ¹H-NMR spectrum of example 2a. C₄₇H₇₅NO4 (718.13).Calculated/recovered: C (78.61/78.59), H (10.53/10.66); N (1.95/1.87).Hyperforin content (titration with HClO₄): 100%.

EXAMPLE NO. 3a

Method B

3,4,5-Trimethoxybenzylamine Salt of Hyperforin.

57.8 mg (0.1 mmol) 93.5% hyperforin is dissolved in 2 ml n-pentane andimmediately reacted with 50 μl of a 2M solution of3,4,5-trimethoxybenzylamine in MTBE. The colourless precipitate is drawnoff by suction, washed with pentane and dried under vacuum at roomtemperature. Yield: 10 mg of a white crystallisate (14% of theoretical).IR: 1480 cm⁻¹ (sv). C₄₇H₆₇NO₇ (734.04).

EXAMPLE NO. 3b

Method C

3,4,5-Trimethoxybenzylamine Salt of Hyperforin.

58.3 mg (0.1 mmol) 92.7% hyperforin is dissolved in 2 ml anhydrousmethanol, reacted with 19.7 mg (0.1 mmol) freshly distilled3,4,5-trimethoxybenzylamine, diluted with 2 ml methanol and evaporatedat 50° C. The evaporate is taken up in 20 ml water and lyophilised.Yield: 70.4 mg of a white powder (96% of theoretical). Mp.: 126-33° C.IR: 1484 cm⁻¹ (sv). C₄₅H₆₇NO₇ (734.04). Hyperforin content: (HPLC):87.2%.

EXAMPLE NO. 4

Method D

L-arginine Salt of Hyperforin.

58.3 mg (0.1 mmol) 92.7% hyperforin is dissolved in 2 ml anhydrousmethanol, reacted with the solution of 17.4 mg (0.1 mmol) L-arginine in0.5 ml bidist. water and 15 ml methanol, and concentrated under vacuumat 50° C. The residue is diluted with 10 ml water and lyophilised.Yield: 58.1 mg of a white powder (81.7% of theoretical). Mp.: Sinteringfrom 110° C., degradation at 145° C. IR: 1486 cm-⁻¹ (sv). C₄₁H₆₆NO6(711.01). Hyperforin content: (HPLC): 82.7%.

EXAMPLE NO. 5

Method B

Pyrrolidine Salt of Hyperforin.

578 mg (1.0 mmol) 93.5% hyperforin is dissolved in 15 ml n-pentane, thenreacted with 85 μl (1.0 mmol) pyrrolidine, and allowed to stand for 24 hat room temperature (no crystallisation) and 24 h at −20° C. (oilyprecipitation of the product). The mixture is evaporated, the evaporatedissolved in water/methanol, and lyophilised. Yield: 576 mg (0.947 mmol)of a colourless powder (94.7% of theoretical). IR: 1489 cm⁻¹ (sv).C₃₉H₆₁NO₄ (607.93). Hyperforin content: (HPLC): 93.7%.

EXAMPLE NO. 6

Method D

Ethylene Diamine Salt with 2 Mol Hyperforin.

58.3 mg (0.1 mmol) 92.7% hyperforin is dissolved in 2 ml methanol,reacted with 50 μl of a 1M solution of ethylene diamine in water and 2ml methanol, and concentrated under vacuum at 50° C. The residue isdiluted with 20 ml water, and lyophilised. Yield: 57.1 mg of a whitepowder (100.7% of theoretical). Mp.: (sintering from 40° C.) 50-2° C.IR: 1480 cm⁻¹ (sv). C₇₂H₁₁₂N₂O₈(1133.70). Hyperforin content: (HPLC):83.1%.

EXAMPLES NOS. 7 to 20

Further examples of hyperforin salts in accordance with the inventionare presented in Table 1 below. After lyophilisation the salts arepresent as colourless or cream-coloured powders. Their composition isconfirmed by NMR- and IR-spectroscopy.

TABLE No. 1 Melting Hyperforin Yield range IR content No. StructureSalt-former Method [%] [° C.] [cm⁻¹] HPLC [% th.] 7

Tris- (hydroxy- methyl)- aminomethane D 88 37-53 1489 sv 90.4 8

2-methyl- aminomethanol D 101 42-50 1491 sv 85.3 9

2-amino-2- methylpropanol D 100 72-5 1487 sv 86.1 10

Chloline C 100 58-61 1505 sv 78.7 11

1-amino-3.5- dimethyl- adamantane (Memantin) C 100 62-70 1487 sv 88.8 12

N-methyl- homoveratryl- amine C 100 47-57 1491 sv 75.0 13

N-methyl-D- glucamine (Meglumin) D 100 48-68 1493 s 76.4 14

1-methyl- piperazine D 95 57-62 1491 sv 92.9 15

N-(3-amino- propyl)- N-cyclo- hexylamine (APCHA) D 100 55-8 1486 sv 90.816

4-amino- pyridine D 92.7 80-2 1486 sv 94.6 17

Imipramine C 100 45-60 1489 s, 1500 s 90.5 18

Desipramine C 100 69-75 1489 ss 90.9 19

Nicotine D 97.5 48-50 1492 s 94.9 20

Selegelin (Deprenyl) C 74 37-47 1495 m 110.2

EXAMPLE NO. 21

Isolation of hyperforin/adhyperforin from a hypericum-CO₂ extractcontent: 32.1% hyperforin, 6.8% adhyperforin) by precipitation asN,N-dicyclohexylamine salt and recrystallisation.

a) 200 g of the extract (145 mmol hyperforin+adhyperforin) is extractedwith 2.8 L n-heptane/isopropanol 98/2 (“98H/I”) in a rotating flask at40°C., 200 g anhydrous sodium sulphate is added, stirred for 30 min,filtered from the undissolved material (Super Seitz 1500 filter plate)and washed with 200 ml “98H/I”. 29 g (160 mmol) dicyclohexylamine isadded dropwise to the filtrate under stirring, and the mixture isallowed to stand for 16 h at 20° C.

The crystallisate is drawn off by suction, washed with “98H/I” and driedunder vacuum (K1: 55.76 g). The mother liquor is concentrated to ⅓ ofthe volume, stored for 16 h at 20° C. and cooled to 4° C. Thesupernatant is decanted from the crystallisate, and the crystallisate iswashed with “98H/I” and dried (K2: 37.95 g).

The raw crystallisate (K1+K2: 93.71 g; HPLC content: 67.2% hyperforin,14.1% adhyperforin) is dissolved in 400 ml (ultra pure) methanol, storedfor 4h at 4° C., precipitated waxy material is drawn off by suction, thefiltrate is concentrated, dissolved in 200 ml MTBE, 300 ml n-pentaneadded, stored for 16 h at 20° C. and cooled to 4° C. The crystallisateis drawn off by suction, washed 2× with cold MTBE/pentane, pre-driedunder vacuum (approx. 20 hPa), and dried at 60° C./0.1 hPa [46.73 g K3;Mp.: 161.6-162.0° C. HPLC content: 84.9% hyperforin, 17.5%adhyperforin]. The mother liquor is concentrated to 2/3 of the volume,stored as above, the crystallisate is drawn off by suction, washed anddried as above [30.92 g K4); Mp.: 158.8-159.2° C. HPLC content: 78.9%hyperforin, 19.2% adhyperforin].

Total yield: 77.29 g dicyclohexylamine salt of hyperforin/adhyperforin(approx. 82/18)=approx. 74%.

b) 1000 g of the extract (725 mmol hyperforin+adhyperforin) is dispersedin 15 L methanol for 15 min at 22-29° C. with an Ultra-Turax, stored for17 h at 4° C., and precipitated wax is filtered off through aSeitz-Supra 2600 single-layer filter. The filter cake is washed with 1 lmethanol, and the combined filtrates concentrated to approx. ⅓ of thevolume. The concentrate, cooled to 20° C., is saturated with heptane,extracted with 3×2 l methanol-saturated heptane, and the combinedextracts re-extracted with 2×500 ml heptane-saturated methanol. Thecombined methanol extracts are evaporated at 40° C., thereafterdissolved in 8 l “98H/I” at 40° C. under rotation, cooled to 20° C.,reacted with 159 ml (798 mmol) dicyclohexylamine under stirring,protection from light, and argon, and the immediately crystallisingmixture is stored for 16 h at 4° C. The crystallisate is drawn off bysuction, washed with “98H/I” and dried under vacuum. The dry product(425 g) is suspended in 1.5 l MTBE, stirred for 5 min at 40° C., thecrystallisate drawn off by suction after cooling to 20° C., washed withcold MTBE, and dried for 24 h at 20° C./10 hPa. Yield: 355.0 g (494mmol)=68.2%. Mp.: 161.0° C. HPLC content: 82.44% hyperforin, 17.39%adhyperforin, together 99.83%.

EXAMPLE NO. 22

Salt of Adhyperforin with Dicyclohexylamine.

The adhyperforin is isolated from a portion of thehyperforin/adhyperforin dicyclohexylamine salt (K4 in example 21) bypreparative HPLC on RP-18 adsorbent (HPLC content: 93.8%). 34 mg (62μmol) of this is dissolved in 2 ml “98H/I” under N₂ and exclusion oflight, 12.5 μl (63 μmol) dicyclohexylamine is added by doping, after 18h the crystallisate is drawn off by suction, washed with cold “98H/I”and dried for 18 h under vacuum. Yield: 12.5 mg (17 μmol)=27%. HPLCcontent: 91.2% adhyperforin.

EXAMPLE NO. 23

Release of Hyperforin/Adhyperforin From a Dicyclohexylamine Salt ofHyperforin/Adhyperforin (HPLC Content: 86% Hyperforin, 15%Adhyperforin).

A suspension of 718 mg (1.0 mmol) hyperforin/adhyperforindicyclohexylamine salt in 60 ml MTBE is prepared, 10 ml 1-molar aqueouscitric acid is added, stirred for 30 min, the MTBE phase is separatedoff, washed 3× with water, dried over sodium sulphate and evaporated.The colour-less oil is dried at 20° C./0.1 hPa. Yield: 527.6 mg (0.983mmol)=98.3%. HPLC content: 86.8% hyperforin, 14.9% adhyperforin.

EXAMPLE NO. 24

Potassium Salt of Hyperforin/Adhyperforin.

537 mg (1.0 mmol) of a hyperforin/adhyperforin -9/1- mixture isdissolved in 100 ml methanol, reacted with 10 ml 0.1M-KOH in methanol,and evaporated. The residue is taken up in 80 ml water and lyophilised.Yield: 590.6 mg (99.6 mmol)=99.6% of a colourless powder. Mp.: 110-112°C. (sintering). HPLC content: 78.7% hyperforin, 8.8% adhyperforin. IR:1499.5 cm⁻¹ (sv). C₃₅H₅₁KO₄×H₂O (592.91).

EXAMPLE NO. 25

Lithium Salt of Hyperforin/Adhyperforin.

2.68 g (5.0 mmol) of hyperforin/adhyperforin -5/1- mixture is dissolvedin 50 ml methanol, reacted with the solution of 0.210 (5.0 mmol) lithiumhydroxide hydrate in 20 ml methanol, the mixture evaporated at 40° C.,the residue dissolved in 30 ml water and lyophilised. Yield: 2.735 g(4.88 mmol)=97.5% of a colourless powder. Melting range: 80-93° C. HPLCcontent: 80.2% hyperforin, 15.0% adhyperforin; together 95.2%. IR:1493.1 cm⁻¹ (sv). C₃₅H₅₁LiO₄×H₂O (560.74).

EXAMPLE NO. 26

L-lysine Salt of Hyperforin/Adhyperforin.

2.68 g (5.0 mmol) of hyperforin/adhyperforin -5/1- mixture is dissolvedin 50 ml methanol, reacted with the solution of 0.731 g (5.0 mmol)L-lysine in 10 ml water, and the clear mixture evaporated at 40° C. Theresidue is lyophilised after addition of 50 ml water. Yield: 3.35 g(4.78 mmol)=95.6% of a colourless powder. Melting range: 74-98° C. HPLCcontent: 83.25% hyperforin, 16.98% adhyperforin; together 100.2%. IR:1483 cm⁻¹ (sv). C₄₁H₆₆N₂O₆×H₂O (701.07).

EXAMPLE NO. 27

Pindolol Salt of Hyperforin/Adhyperforin.

2.68 g (5.0 mmol) of hyperforin/adhyperforin -8/1- mixture and 1.24 g(5.0 mmol) pindolol are dissolved in 50 ml methanol and evaporated at40° C. The residue is lyophilised after addition of 50 ml water. Yield:4.03 g (5.1 mmol)=102% of a white foam. Melting range: 65-75° C. HPLCcontent: 91.2% hyperforin, 11.7% adhyperforin; together 102.9%. C₄₉H₇₂N₂O₆ (701.07).

EXAMPLE NO. 28

Pyrrolidine Salt of Hyperforin/Adhyperforin.

531 mg (0.99 mmol) of hyperforin/adhyperforin -5/1- mixture is dissolvedin 10 ml methanol under exclusion of light, then reacted with 83.5 μl(0.98 mmol) pyrrolidine and concentrated on a rotary evaporator. Theconcentrate is taken up in 70 ml water and lyophilised. Yield: 570.6 mg(0.938 mmol)=95%. Melting range: 50-70° C. HPLC content: 79.5%hyperforin, 16.4% adhyperforin; together 95.9%. IR: 1489 cm⁻¹ (sv).C₃₉H₆₁NO₄ (607.93).

EXAMPLE NO. 29

Desipramine Salt of Hyperforin/Adhyperforin.

2.68 g (5.0 mmol) of hyperforin/adhyperforin -5/1- mixture is dissolvedin 9/1 MTBE/pentane by warming under N₂ and exclusion of light underaddition of a few drops of methanol, and then crystallised at −20° C.The crystallisate is drawn off by suction, washed with ice-cold 9/1pentane/MTBE, and dried at RT/0.1 hPa. Yield: 4.03 g (5.0 mmol)=100% ofa white crystalline powder. Mp.: 154.8-155.3° C. HPLC content: 82.4%hyperforin, 16.3% adhyperforin; together 98.7%. IR: 1489 cm⁻¹ (sv).C₅₃H₇₄N₂O₄ (803.19).

EXAMPLE NO. 30

Hyperforin/Adhyperforin Sodium Salt.

5.94 g (11.1 mmol) of hyperforin/adhyperforin -9/1- mixture is dissolvedin 50 ml methanol under N₂ and exclusion of light, reacted with 10.7 ml1M-NaOH, and the methanol drawn off in a rotary evaporator at 40° C.under vacuum. The residue is taken up with 50 ml water and lyophilised.Yield: 6.2 g (11.1 mmol)=97.2% of a white powder. Melting range:109-128° C. HPLC content: 91.3% hyperforin, 9.5% adhyperforin; together100.8% of the theoretical value. IR: 1499 cm³¹ ¹ (sv). C₃₅H₅₁NaO₄×H₂O(576.80).

EXAMPLE NO. 31

L-arginine Salt of Hyperforin/Adhyperforin.

2.68 g (5.0 mmol) of hyperforin/adhyperforin -5/1- mixture is dissolvedin 50 ml methanol under N₂ and exclusion of light, reacted with thesolution of 0.87 g (5.0 mmol) L-arginine in 10 ml water, andconcentrated under vacuum at 50° C. The residue is diluted with 50 mlwater and lyophilised. Yield: 3.59 g (4.92 mmol)=98.5% of a whitepowder. Melting range: 115-133° C. IR: 1486 cm⁻¹ (sv). HPLC content:82.6% hyperforin, 17.0% adhyperforin; together 99.6%. C₄₁H₆₆NO₆×H₂O(729.02).

EXAMPLE NO. 32

Stability of Hyperforin Salts.

Samples of hyperforin salts are stored in brown-glass bottles withsnap-on caps at room temperature without protective gas, and thehyperforin (examples 1 to 20) or hyperforin+adhyperforin (examples 21 to31) content is determined by HPLC (area%/o) at the storage times 0, 1week, 4 weeks and 12 weeks. The changes in the hyperforin(+adhyperforin) content are presented in Table II.

TABLE II Stability of hyperforin salts Change in the hyperforin content(% of the stoichiometric content) Substance Dif- Dif- Dif- accordingference ference ference to after after after Example Initial 1 week 4weeks 12 weeks No. value [%] [%] [%] [%] Comments  1 85.9 −0.4 −2.3  2100 ±0.0 Reference (titr.)¹⁾ (titr.)¹⁾ standard for HPLC  3 87.2 +1.1−1.1 −5.0  4 82.7 −0.9 −2.8 −6.0  5 93.7 −0.5 ±0.0 −3.2  6 83.1 −4.8  790.4 −3.1  8 85.3 +1.2 −6.0  9 86.1 +1.8 −4.1 −9.5 10 78.7 −3.3 −8.8 1188.8 −0.9 −3.0 −11.5  12 75.0 +0.3 −5.3 −5.6 13 76.4 +0.9 −1.6 −2.8 1492.9 −0.5 −4.5 −10.4 15 90.8 −2.0 −2.0 −9.9 16 94.6 +1.4 +0.1 ±0.0 1790.5 −0.8 −5.6 −12.6  18 90.9 +1.5 +2.1 −2.6 21 98.4 −0.9  −1.5** **8weeks 25 93.2 −3.7 26 97.7 +0.2 −2.7 −5.1 27 102.9 +0.5 −0.8 −0.2 2895.9 −0.7 −1.1 −4.7 29 98.7 +0.9 +1.3 +1.0 30 98.6 −0.4 Free 91.5 −17.9 −24.25 −28.4  Comparison hyperforin

1 This salt is used as the reference standard. The hyperforin content(in % of the calculated chiometric value) was determined by means ofperchloric-acid titration. The values obtained confirm the increasedstability and improved storage stability of the hyperforin salts ascompared with free hyperforin.

EXAMPLE NO. 33

Activation of Protein Kinase PKCγ by Hyperforin and its Salts.

PKCγ activators are potentially suitable for activating cc-secretase.These activators are found in enzyme tests in which the recombinantlyproduced PKC-γ is suboptimally active. The test media were:

HEPES-NaOH 50 mM EDTA 1 mM EGTA 1.25 mM MgCl₂ 5 mM DTT 1 mM ATP 0.1 μMHiston III-S 100 μg/ml Recombinant PKC-γ 200-100 ng/well CaCl₂ 1.32 mM

Table III below presents the activity increases of recombinant PKC-γ dueto hyperforin and its salts in various concentrations.

TABLE III Activation of protein kinase PKC-γ Increase in the activity ofPKC-γ [%] at the substance dose: Example No. 10 μg/ml 3 μg/ml 1 μg/mlHyperforin 45 51 6  1 56 30 9  5 48 20 3 21 56 22 −9  24 21 24 7 25 4512  26 43 20 10  27 34 18 6 31 24  7 5 1% DMSO  6  5 4

In the table, the control with 100 nM phorbol-12-myristate-13-acetate(TPA; stimulator of PKC-γ) was set to 100%.

The values determined reveal a distinct increase in the PKC-γ activitywhen hyperforin or its salts is added to the test medium.

EXAMPLE NO. 34

Activation of α-secretase Due to Hyperforin and its Salts.

In order to be able to demonstrate the α-secretase activity in acellular test system independently of β- and γ-secretase, an expressionplasmid composed of DNA cassettes of APP (Alzheimer Precursor Protein)and APLP-2 (Alzheimer Precursor-like Protein-2) and of the reporterprotein Seap (sereted alkaline phosphatase) was designed (see FIG. 1).

As the APP cassette in both constructs begins with amino-acid 7 of theβ-amyloid sequence, the recognition sequence for β-secretase in thesec-fusion proteins is absent. Cleavage by γ-secretase has not beendescribed for human APLP-2, with the result that the specificity of thefusion proteins for α-secretase only is achieved by substitution of thetrans-membrane domain of APLP-2 for APP. The expression plasmid secα1was stably transfected into human neuronal cells SY5Y. Activation ofα-secretase in these secα1-transfected cells is manifested in anincreased release of Seap into the cell medium. The quantity of Seap isdetermined, and serves as a measure of the α-secretase activity.

Test conditions: 80 000 FL-2a cells/well. V=100 μl. Incubation time: 60min.

Concentration of the substances: 10 μg/ml.

Mean values±s.d. of triplicates.

In Table IV below, the quantities of secreted alkaline phosphatase(Seap) measured in relative light units (RLU) are displayed as a measureof stimulation of the α-secretase activity by hyperforin and its salts.

TABLE IV Activation of α-secretase Activity of α- secretase Example No.[RLU] s.d. [RLU] Comments Hyperforin 441 55.1 21 350 14.6 24 445 67.1 25322 128.6  26 423 34.4 27 453 15.1 28 457 42.9 29 404  8.9 30 419 41.931 481 42.6 DMSO  76  8.9 Solvent control TPA 386 11.4 Positive control

The activation of α-secretase by the phorbol ester TPA (100 ng/ml) wasmeasured as the positive control.

The measured values reveal marked activation of α-secretase both whenhyperforin and when its salts are added to the test medium.

What is claimed is:
 1. Salts of hyperforin and adhyperforin of formula I[A⁻]m[B]^(p+)  (I) in which m is a whole number from 1 to 3,

and [B]^(p+) is an ion of an alkali metal or an ammonium ion of asalt-forming nitrogen base of formula III

 wherein R1, R2 and R3 independently of one another, are a hydrogenatom, a straight-chain or branched alkyl, cycloalkyl, bicycloalkyl,tricycloalkyl, alkenyl, alkynyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl or heteroarylalkyl group, or a derivative of the said groupswhich include one or more hydroxy, alkoxy, aryloxy, alkanoyl, aroyl,carboxy, alkoxycarbonyl, amino, alkylamino, hydroxylamino, carboxamidohaving the formula (lower alkyl) —CO—NH—, carbamoyl, ureido, amidino,guanidino, cyano, azido, mercapto, alkylthio, alkylsulphonyl,alkylsulphenyl, aminosulphonyl, fluoro, chloro, bromo, iodo, alkyl orperfluoroalkyl groups, or wherein the residues R1 and R2 together withthe N atom are an azetidine, pyrrolidine, pyrroline, piperidine,piperazine, homopiperazine, morpholine, thiomorpholine, pyridine, di- ortetrahydropyridine, pyrimidine, pyrazine, azepine, thiomorpholine,pyridine, di- or tetrahydropyridine, pyrimidine, pyrazine, azepine,dihydroazepine, oxazepine, diazepine, imidazole, pyrazole, oxazole, orthiazole ring, or one of the said rings which exhibits aliphatic,heteroaliphatic, aromatic or heteroaromatic rings condensed on to itand/or is substituted with one or more hydroxy, alkoxy, aryloxy,alkanoyl, aroyl, carboxy, alkoxycarbonyl, amino, alkylamino,hydroxylamino, amido, carbamoyl, ureido, amidino, guanidino, cyano,azido, mercapto, alkylthio, alkylsulphoxy, alkylsuphonyl,alkylsulphenyl, aminosulphonyl, fluoro, chloro, bromo, iodo, alkyl orperfluororoalkyl residue(s), and wherein the residue R4 is a hydrogenatom or a straight-chain or branched alkyl group, in which p=m and givethe total number of positive charges of the residue [B].
 2. Saltsaccording to claim 1 in which the alkali-metal ion is a lithium, sodiumor potassium ion.
 3. Salts according to claim 1, in which thesalt-forming nitrogen base is selected from the group composed ofaliphatic and cycloaliphatic amines, aliphatic and cycloaliphatic aminessubstituted with one or more hydroxyl groups, polyamines, cyclic andheterocyclic amines, cyclic or heterocyclic amines substituted with oneor more lower alkyl or hydroxyl residues, unsubstituted and substitutedaromatic, heteroaromatic, arylaliphatic and heteroarylaliphatic amines,and lower alkyl esters, amides or lower alkylamides of natural α-, β-,γ-, δ-, ε-, or ω-amino carboxylic acids.
 4. Salts according to claim 3in which the salt-forming nitrogen base is N,N-dicyclohexylamine.
 5. Thesalts of claim 1 or claim 3 wherein said salt-forming nitrogen base isselected from the group consisting of N,N-dicyclohexylamine,trimethoxybenzylamine, 2-amino-2-methylpropanol, pyrrolidine,N-methyl-D-glucamine, 1-amino-3,5-dimethyladamantane, 4-aminopyridine,L-arginine, L-lysine, Desipramine, and Pindolol.
 6. A pharmaceuticalpreparation for the treatment of Alzheimer's Disease and the symptomsassociated with it, comprising a safe and effective amount of at leastone salt of any one of claims 1 to 4, together with apharmaceutically-acceptable carrier.
 7. A method of manufacturing thesalts of hyperforin and adhyperforin according to one of claims 1 to 4,in which hyperforin and/or adhyperforin are dissolved under inert gas ina solvent or solvent mixture selected from the group composed of C₅-C₈alkanes or cycloalkanes, lower chloroalkanes, alcohols, ketones, estersand ethers, and combined in the desired stoichiometric ratio with thesolution of an alkali-metal base or a salt-forming nitrogen base in oneof the aforementioned solvents or in water, after which the salt formedis allowed to crystallise out and separated or the combined solvents areevaporated and lyophilised after addition of water.
 8. A method ofenriching or purifying hyperforin and adhyperforin in the form of thesalts according to one of claims 1 to 4 from St. John's wort extracts,characterised in that a St. John's wort extract with a total content ofhyperforin and adhyperforin of 20-80%, is dissolved in a suitablesolvent selected from the group composed of apolar C₁-C₁₀ alkanes andC₁-C₁₀ cycloalkanes, and this solution is reacted with an at leastequimolar quantity of an alkali-metal base or a salt-forming nitrogenbase or a solution of one of these bases in one of the above-mentionedsolvents or in a C₁-C₄ halogenoalkane, ether, tetrahydrofuran or ketoneand the salt produced is separated, purified and dried.
 9. A methodaccording to claim 8, characterised in that N,N-dicyclohexylamine isused as the base.
 10. A method of stabilizing hyperforin, adhyperforinand mixtures thereof comprising obtaining an extract having 20 to 80%hyperforin/adhyperforin dissolved in a suitable solvent, reacting saidextract with a nitrogen base to form one or more of the salts as claimedin claim 1, and separating said salts from said reaction mixture.